BCL2 Inhibition in Leukemia - Episode 8

Initiating Therapy in Patients With CLL

Harry Erba, MD, PhD:Please join me in welcoming my colleague, Dr Javier Pinilla-Ibarz, a senior member and the head of the lymphoma section at Moffitt Cancer Center in Tampa, Florida. Welcome, Dr Pinilla-Ibarz. Let’s get started. Let’s begin with a discussion of the goals of therapy for patients with chronic lymphocytic leukemia [CLL].

Javier Pinilla-Ibarz, MD, PhD:Harry, as you know, chronic lymphocytic leukemia is a disease of older people, a median age of 70, 72 years old. And all these people may have already multiple comorbid conditions. Most of the time, 70% to 80% do have those, right? The goals of therapy are really how to be customized to each of these patients. But for sure, continuing to improve and to maintain the quality of life for the older population of patients who really have this disease is very, very important. No doubt the quality of life can be achieved by really obtaining very good responses or maintaining these responses for longer period of time.

Harry Erba, MD, PhD:Tell us a little more about how you approach staging in these patients and prognostication?

Javier Pinilla-Ibarz, MD, PhD:The staging of CLL is very well defined for many years through the Rai classification and the Binet classification, where we really differentiate early stage versus stages where patients require therapy. However, over the last 20 years, many more prognostic factors have been incorporated to see how these patients are going to behave. What I mean is that diagnosis of CLL is very common, but most of the patients at diagnosis won’t require therapy. However, when we study certain genetic features, like chromosomal abnormalities by FISH [fluorescence in situ hybridization] analysis orIGHVstatus by molecular techniques, we can really predict who are the patients who may require therapy sooner rather than later and in some cases or the patient who may never require therapy because they have very, very indolent course.

Harry Erba, MD, PhD:Do all patients require therapy at the time of diagnosis?

Javier Pinilla-Ibarz, MD, PhD:No, it’s exactly what I was trying to explain. Most of the patients won’t require therapy at diagnosis. However, over time, and depending on these prognostic futures by cytogenetics ofIGHV-mutated status, they may require therapy sooner or later.

Harry Erba, MD, PhD:How do you decide when a patient requires therapy? What are the indicators?

Javier Pinilla-Ibarz, MD, PhD:That’s a great point. It’s very well studied and well documented. In fact, last year we had the iwCLL [International Workshop on CLL] 2018 review criteria, and they pretty much didn’t change from 10 years before. We still really follow patients for long periods of time, and when they show cytopenias, hemoglobin less than 10 g/dL, platelet count than 100 per mm3, growth or enlargement of the lymph nodes, splenomegaly, or B-cell symptomatology, those are pretty much the classical reasons why we really decide to start to have the conversation about which therapies will be the more optimal for each patient.

Harry Erba, MD, PhD:In the Rai staging system, it would be intermediate and high-stage patients and not the stage 0 patient, typically.

Javier Pinilla-Ibarz, MD, PhD:That’s correct. And although the Rai staging system still is used for really defining patients and how they’re going to behave, more and more we rely on these iwCLL criteria to start therapy. They’re very, very well documented.

Harry Erba, MD, PhD:You started a discussion about this, but why don’t you discuss what the diagnostic and risk stratification tests are that you get at the time of diagnosis or when you’re thinking about beginning therapy.

Javier Pinilla-Ibarz, MD, PhD:That’s a really good point. Some people can argue diagnosis of flow cytometry in peripheral blood may be good enough to establish the diagnosis. However, some patients really want to demand how this disease is going to behave. Right now, there is no really formal indication to all these tests for diagnosis, but for sure before therapy. However, more and more people really want to really see how this disease is going to behave. Right now, I think a FISH analysis is really looking for the 4 most common chromosomal abnormalities: 13q, trisomy 12, 11q, and 17p.TP53mutation is mandatory for sure before therapy.TP53by sequencing is something that also has been incorporated as a very, very useful tool before starting therapy. Because we know that there are certain patients who are not deletion of 17p, but they may carry theTP53mutation.

As you know, there are 2 different techniques. One is FISH and 1 is sequencing, right? Besides that, I think the other very, very important thing based on the publication and based on the data that we have with the era of chemoimmunotherapy is the status of the IGHV in the surface of the B cell. We know that mutated immunoglobulin genes really behave more indolent and unmutated immunoglobulin genes are really more aggressive over the course of the disease.

Harry Erba, MD, PhD:That’s a very fine point, this mutational status of the immunoglobulin variable region gene. And I’m not sure many practicing oncologists understand where that comes from. My understanding is about 50% will have mutated.

Javier Pinilla-Ibarz, MD, PhD:That’s correct, Harry. That’s correct.

Harry Erba, MD, PhD:What it really indicates is when the neoplastic transformation or where the neoplastic transformation occurred, was it in a pregerminal center lymphocyte or 1 that’s already seen…

Javier Pinilla-Ibarz, MD, PhD:Pre- or postgerminal center.

Harry Erba, MD, PhD:Yes, postgerminal center. Those are mutated, and those are the ones that have a better prognosis.

Javier Pinilla-Ibarz, MD, PhD:That’s correct.

Harry Erba, MD, PhD:Do you do karyotypic analysis?

Javier Pinilla-Ibarz, MD, PhD:That’s another very interesting point. More recently, with the introduction of targeted therapy, we really found out that karyotypic analysis is also useful to differentiate patients who may have high risk to progress even in the presence of these new targeted molecular drugs. Traditionally, we didn’t do that because it’s hard to really have conventional cytogenetics. But today with techniques like the use of CpG and IL-1, we can really have some metaphases. Obviously in aggressive patients it’s easily obtained. And we can really have a better characterization of how aggressive this disease may behave in the long-term.

Harry Erba, MD, PhD:Let me ask you a loaded question. How about a patient who is asymptomatic and does not have adenopathy, splenomegaly, or low blood counts but has a high-risk score by P53 deletion, mutation, or other features? Should that patient be treated early, or should they still be watched?

Javier Pinilla-Ibarz, MD, PhD:We still don’t have data to really suggest that we should treat early on, even in a patient who has high prognostic features. In this case, you almost refer to the IPI [International Prognostic Index] or CLL-IPI score, which really, really put a lot of emphasis in theIGHV, unmutatedTP53, or deletion of 17p. So with the patients who we know are most likely going to progress very, very soon after diagnosis, sometimes it’s not really uncommon to see at diagnosis that they require therapy. However, right now, we don’t have evidence historically with any other types of CLL showing that treating this patient early can really prolong survival. This is true is that this is an important matter or important subject to investigation, that for sure we’re going to really start to see in the next year in terms of clinical trials.

Harry Erba, MD, PhD:Yes, and exactly the NCI [National Cancer Institute] has actually approved a SWOG concept that was developed in the intergroup looking at intervention for those patients with high-risk disease.

Javier Pinilla-Ibarz, MD, PhD:Absolutely. And we’re going to see more and more. We have in our institution another clinical trial asking the same question: should we intervene early in these high-risk patients? But we still don’t know the answer.

Transcript edited for clarity.